Facial palsy as a manifestation of COVID‐19: A systematic review of cases

Abstract Background and Aims Facial palsy is a rare complication of the COVID‐19 infection. Herein, we conducted a systematic review of all published cases of facial palsy post‐COVID‐19 infection in an attempt to educate the general population and medical practitioners regarding the likely occurrence of facial palsy in COVID‐19 patients, its detection, effective treatment plan, and prognosis of the condition. Methods We searched PubMed, Google Scholar, and Directory of Open Access Journals (DOAJ) from December 1, 2019 to September 21, 2021. Results We included 49 studies bearing accounts of 75 cases who had facial palsy. The mean age of patients was 42.9 ± 19.59 years, with a male‐to‐female ratio of 8:7. The majority of the cases were reported from Brazil (n = 14), USA (n = 9), Turkey (n = 9), and Spain (n = 9). Noticeably, 30.14% of COVID‐19 patients were diagnosed with Guillain‐Barré syndrome. In total, 22.97% of patients complained of bilateral facial paralysis (n = 17), whereas ipsilateral paralysis was observed in 77.03% (n = 57). These were common complaints of Lagophthalmos, otalgia, facial drooping, dysarthria, and compromised forehead wrinkling. The treatment regimen mainly included the use of corticosteroids (n = 51) (69.86%), antivirals (n = 23) (31.51%), IVIG (n = 18) (24.66%), antibiotics (n = 13) (17.81%), antiretroviral (n = 9) (12.33%), and antimalarial (n = 8) (10.96%) medications. In all, 35.62% of patients (n = 26) adhered to a combination of antiviral and corticosteroid‐based therapy. Positive treatment outcomes were observed in 83.58% (n = 56) of cases. In contrast, 10 patients (14.93%) showed nonsignificant recovery, out of which 3 (4.48%) died from the disease. Conclusion The association of facial palsy with COVID‐19 is controversial and therefore requires further investigation and published work to confirm a causal relationship. However, physicians should not overlook the likelihood of facial palsy post‐COVID‐19 infection and treat it accordingly.


| INTRODUCTION
On December 31, 2019, a novel coronavirus was first identified in Wuhan, China, after reports of multiple cases of pneumonia among its people. 1 This was the start of an outbreak that took the shape of a pandemic over a few months, owing to its rapid transmission through respiratory droplets. As of May 10, 2022, 6.53% of the world population (n = 515,748,861) has confirmed infection with COVID-19, while 1.21% of these have lost their lives to the complications of COVID-19. 2 COVID-19 patients commonly complain of fever, fatigue, nasal congestion, myalgia, anosmia, dry cough, ageusia, hemoptysis, dyspnea, and so forth. 3 Under more serious circumstances, COVID-19 can result in severe pneumonia, acute respiratory distress syndrome, sepsis, septic shock, multiple organ failure, and so forth. 4 While these are some of the most widely reported complications of  infection, other less common ones have also surfaced, for example, hemophagocytic lymphohistiocytosis (HLH), vasculitis, central retinal vein occlusion, and so forth. [5][6][7] Similarly, facial palsy has emerged as an unusual yet interesting complication of COVID-19, whose pathophysiology is yet to be known.
Numerous case reports and series documenting facial palsy as a complication of COVID-19 have been published. In addition, some systematic reviews have discussed the association of facial palsy with COVID-19. However, none of these reviews collectively assessed all the cases of facial palsy secondary to COVID-19. For instance, Gupta et al. 8 included only those cases in which facial palsy was an isolated neurological finding. Therefore, in our systematic review, we aim to develop a stronger evidence base by including all the cases of facial palsy secondary to COVID-19 that have been published to date.
Moreover, we generated patient-level data by including case reports to thoroughly evaluate the patient characteristics and clinical course of facial palsy secondary to COVID-19. This will not only bridge the gap in literature but will also aid physicians in reaching a timely diagnosis and in devising treatment regimens that cater to the patients' individual needs.

| Literature review
Our work aligns with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist (Supporting Information: File S1). 9 We searched PubMed, Google Scholar, and Directory facial palsy (e.g., facial palsy OR facial weakness OR facial paresis OR bell's palsy). The Reference section of included studies was also checked for completeness' sake. Please refer to our Supporting Information: File S1 for a detailed search strategy. Furthermore, this study is registered in the International prospective register of systematic reviews (PROSPERO) and holds the unique identifying number (UIN); CRD42022324693. 10

| Inclusion and exclusion criteria
Our search criteria included all case reports, case series, editorials, correspondence, and retrospective cohorts on the topic of facial palsy following COVID-19 infection. Only work published in English and containing comprehensive detail of clinical presentation and progression of the condition in each patient was included in our systematic review.
Studies bearing aggregate level data, language barriers, and incomplete detail of the condition were excluded from our study. The title, abstract, and full-text screening were completed in duplicate and independently by two reviewers (M.K. and A.S.). Disagreements regarding the inclusion of studies for data extraction were resolved by the senior author (A.K.).

| Data extraction
Duplicate work was removed after a final version of included literature was entered on excel sheets. We gathered available data on the origin of the reported case (country), date of publication, study type, relevant case within every included study, patient characteristics, age, sex, the status of Guillain-Barré syndrome (present or absent), affected side of the face, the onset of facial palsy, the test used for detection of COVID-19, features related to facial palsy, results of cerebrospinal fluid (CSF) analysis, COVID-19 related symptoms, other signs/symptoms, imaging results, treatment regimen and outcome of treatment. Due to a lack of uniformity in the assessment of facial symptoms between included studies, the percentage-wise prevalence of symptoms could not be calculated. Additionally, since follow-up time varied between studies, treatment follow-up results are not comparable. The terms "complete recovery," "partial recovery," "progressive improvement," and "significant improvement" were regarded as positive treatment outcomes by the author of this review.

| Quality assessment
The quality of included cases was assessed using Joanna Briggs institute's critical appraisal tools. 11 Selected studies were examined for inclusion criteria, sample size, description of study participants, and setting. Two reviewers independently assessed the methodological quality of each paper. Quality assessments were done with different tools based on different study designs. Each tool was modified to provide a numeric score. Tools had 8 items for case reports and 10 for case series. Included case reports (n = 39) had a mean score of 6.385 ± 1.41 with scores ranging from 2 to 8 12-50 10 case series had a mean score of 5.60 ± 2.01, and scores ranged from 3 to 9. [51][52][53][54][55][56][57][58][59] The detailed results of the quality assessment are provided in Supporting Information: File S1. The quality of our systematic review was assessed using AMSTAR 2 criteria. 60 The level of compliance with AMSTAR 2 came out to be "low." We could not conduct a meta-analysis because only case reports and case series were included in the analyses without quantitative data.

| Statistical analysis
This systematic review reported descriptive information using individual-level data of 75 cases from a total of 49 studies reported on facial palsy as a manifestation of COVID-19. The data focused on the date and country of publication, patient's characteristics, detailed symptoms of facial palsy and COVID-19, the status of Guillain-Barré syndrome (present or absent), results of imaging and Cerebrospinal Fluid (CSF) analysis, treatment plan and its outcome. In addition, the continuous variable's mean, median, and SD were calculated where possible.

| RESULTS
Our initial search provided 1408 results. After removing duplicate studies (N = 1006), 347 studies were screened individually by the two reviewers (M.K. and A.S.). Two hundred and sixteen studies were rejected after going through their titles and abstracts, while full-text versions of the remaining articles (N = 131) were opened to ascertain their relevance to the topic. Out of these, 82 were excluded for reporting aggregate-level data (N = 35), not being of the desired study type (N = 12), not being in English (N = 19), or for reporting insufficient data on medical manifestation (N = 16). Finally, 49 studies met our inclusion criteria and were, thus, included for systematic analysis (Figure 1).

| Symptom presentation
Noticeably These included complaints of fever, fatigue, cough, ageusia, and headache.  However, only two patients used antivirals without corticosteroids to treat facial palsy. A systematic review supports this finding by demonstrating that corticosteroids alone were superior to antivirals alone in treating facial palsy. There was no clear benefit from antivirals alone over placebo. 83 Our findings show that the successful regimens in treating facial palsy due to other etiologies are also effective in treating facial palsy secondary to COVID-19.

| Treatment regimen and disease prognosis
Positive treatment outcomes were observed in 83.58% of patients. This corroborates the effectiveness of the treatment regimens used in the case reports to treat facial palsy secondary to COVID-19. A favorable response to treatment has also been shown in other complications that arise secondary to COVID-19, such as central retinal vein occlusion. 7 However, some complications, such as hypoxic encephalopathy, have also shown a poor prognosis. 84 Thus, this highlights that many distinct complications can arise due to COVID-19 with differing pathogenesis and severity.
There were some limitations in our study. Due to lack of provision of pertinent analytical data, no meta-analysis could be conducted on the topic to confirm the relationship between COVID-19 and facial palsy.
Our review only comprised of case reports/series in which a limited number of patients were assessed. Therefore, large-scale studies with more patients and longer follow-ups are warranted to reliably draw the correlation between COVID-19 and facial palsy. Moreover, studies in languages other than English were excluded from the analyses. Lastly, adequate representation of most countries was not seen in our review, which implies that many cases went unreported there, so they could not be included in our analyses. Despite the limitations, we tried to include all relevant cases to date and demonstrated an in-depth comparison of clinical, radiological, and diagnostic features of COVID-19 and concomitant facial palsy in our patient-level analyses.

| CONCLUSION
To the best of our knowledge, this is the most updated review of

ACKNOWLEDGMENTS
Open Access funding was provided by the Qatar National Library.

CONFLICT OF INTEREST
Abdulqadir J. Nashwan is an Editorial Board member of Health Science Reports and co-author of this article. He is excluded from editorial decision-making related to the acceptance of this article for publication in the journal. The remaining authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The authors confirm that the data supporting the findings of this study are available within the article and its Supporting Information.

TRANSPARENCY STATEMENT
The lead author Abdulqadir J. Nashwan affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.